The production technology for simvastatin, heretofore known, includes (1) the process comprising hydrolysis of lovastatin with lithium hydroxide, lactonization to give a diol lactone, selective silylation with TBDS, acylation and desilylation (U.S. Pat. No. 4,444,784), (2) the process in which lovastatin potassium salt is directly methylated (U.S. Pat. No. 4,582,915), and (3) the process in which lovastatin monoalkylamide is directly methylated (U.S. Pat. No. 4,820,850), among others.
The above process (1) requires a high temperature and a long time for the hydrolysis reaction so that both yield and productivity are low. Moreover, the selective silylation and subsequent steps are not satisfactory enough in reaction selectivity so that the total yield is not as high as desired. In the process (2), the starting lovastatin partially remains unreacted so that a complicated procedure is required for purification. In the process (3), the reaction must be conducted at an extremely low temperature. Thus, all of the processes have much to be improved for commercial-scale production.